This invention relates to an improved process involving decarboxylation. Specifically, it involves the preparation of 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives via selective decarboxylation.
Decarboxylation via heterolytic cleavages generally fall into two catagories:
I. Decarboxylation of acids whose anions are less stable with respect to decarboxylation than the unionized acid; and
II. Decarboxylation of acids whose unionized form is more susceptible to decarboxylation than their anions.
For most acids, decarboxylation (Catalogue I) takes place in a basic medium, i.e., in their anion forms. However, for .alpha. or .beta.-keto acids, decarboxylation (Catalogue II) is usually carried out in an acidic medium, i.e., in their un-ionized free acid forms. 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids are useful anti-inflammatory agents of the structural formula (I). ##STR1## These compounds have been previously prepared in five steps (U.S. Pat. No. 4,089,969) as shown below: ##STR2##
The prior art decarboxylation as described above is usually conducted at relatively high temperatures such as 250.degree. C. To preserve selectivity of decarboxylation under the high temperatures, protection of the 1-carboxylic acid function becomes necessary. Accordingly, two extra steps, i.e.,
(a) the preparation of the monoester (II); and PA0 (b) the hydrolysis of ester (III) to afford (I) are added to the process making it a 5-step process. PA0 R is H; lower alkyl especially C.sub.1-6 alkyl such as methyl, ethyl, n-propyl, butyl, pentyl or hexyl; or halo especially Cl, F, or Br; comprising acidic decarboxylation of a compound of the structural formula (V): ##STR5## wherein Ar and R are as previously defined; and R.sup.1 and R.sup.2 independently are H, t-butyl, benzhydryl or other protecting groups which are easily removed in trifluoroacetic acid or other related organic acids.
As expected, the overall yields of the prior art process are generally lower due to the additional steps and the drastic condition of the decarboxylation.
To the contrary, the present process relates to a selective decarboxylation whereby compounds of formula (I) are unexpectedly prepared from diacid (IV) under mild conditions, for example: ##STR3## As shown above, the tedious blocking and deblocking steps are eliminated, and the drastic decarboxylation condition is avoided. Both contribute to the improved yield of compound (I).